There is a vital need to find drugs that halt or reverse Alzheimer's disease (AD). AD presently affects 18 million people worldwide. The human and financial costs of AD in the US is expected to exceed $150 billion in 2005. FDA approved medications treat symptoms, but do not alter AD progression.
The hallmarks of AD are inter-neuronal plaques consisting of precipitates or aggregates of amyloid beta protein (Aβ), and intra-neuronal neurofibrillary tangles (NFTs) of tau protein. The major target for drug discovery for AD has been Aβ that forms insoluble senile plaques. Although the etiology of AD is not fully understood, the Aβ amyloid cascade hypothesis is the most common view of the pathological pathway of AD in which the generation of Aβ and accumulation of Aβ aggregates in the brain initiate the disease process. It is supported by genetic evidence that mutations leading to increased production of Aβ leads to familial AD. Agents that dissolve Amyloid plaque or reduce plaque burden via other mechanisms are considered potential Alzheimer's drugs.
Development of Water-Soluble Curcumin Derivatives for AD
Curcuma longa commonly referred to as “turmeric” is used as a spice in South Asian cooking, as a cosmetic and in the ancient Ayurvedic system of medicine2-4. There has recently been tremendous interest in curcumin, [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene 3,5-dione] the primary active ingredient in turmeric, because it has been shown to have antioxidant5, anticancer6, anti-inflammatory7, and potent anti-AD activity8. Encouraging results have been published regarding neuroprotective effects of curcumin and ongoing pilot clinical trials have been initiated9. Curcumin has been shown to reduce pathology in AD mouse models overproducing Aβ10-14 and bisdemethoxycurcumin was reported to improve the innate immune system by enhancing phagocytosis of Aβ15. Curcumin appears to have multiple neuroprotective mechanisms including inhibition of inflammation, suppression of Aβ production, reduction of reactive oxygen species by chelating metals, inhibition of stress pathways and induction of heat shock proteins8, 16-18. One of the major limitations of using curcumin as a drug is its poor water and plasma solubility; even doses as high as 8 g of curcumin per day administered to human subjects result in an average peak serum concentration of ˜1.77 μM of curcumin19,20.